6-methyl-N-(2-naphthyl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine | 1393709-13-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 6-methyl-N-(2-naphthyl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine
• 英文别名: 6-methyl-N-naphthalen-2-yl-[1,2,4]triazolo[4,3-b]pyridazin-8-amine
• CAS: 1393709-13-1
• 化学式: C₁₆H₁₃N₅
• 分子量: 275.313
• InChiKey: XOZAIDMDJNOPDH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  55.1
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  6-methyl-5H-[1,2,4]triazolo[4,3-b]pyridazin-8-one 在 palladium diacetate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 sodium t-butanolate 、 三氯氧磷 作用下， 以 甲苯 为溶剂， 反应 0.75h， 生成 6-methyl-N-(2-naphthyl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine
  参考文献：
  名称：

  Bioisosteric Transformations and Permutations in the Triazolopyrimidine Scaffold To Identify the Minimum Pharmacophore Required for Inhibitory Activity against Plasmodium falciparum Dihydroorotate Dehydrogenase

  摘要：

  Plasmodium falciparum causes approximately 1 million deaths annually. However, increasing resistance imposes a continuous threat to existing drug therapies. We previously reported a number of potent and selective triazolopyrimidine-based inhibitors of P. falciparum dihydroorotate dehydrogenase that inhibit parasite in vitro growth with similar activity. Lead optimization of this series led to the recent identification of a preclinical candidate, showing good activity against P. falciparum in mice. As part of a backup program around this scaffold, we explored heteroatom rearrangement and substitution in the triazolopyrimidine ring and have identified several other ring configurations that are active as PfDHODH inhibitors. The imidazo[1,2-a]pyrimidines were shown to bind somewhat more potently than the triazolopyrimidines depending on the nature of the amino aniline substitution. DSM151, the best candidate in this series, binds with 4-fold better affinity (PfDHODH IC50 = 0.077 mu M) than the equivalent triazolopyrimidine and suppresses parasites in vivo in the Plasmodium berghei model.

  DOI：

  10.1021/jm300351w

文献信息

• Bioisosteric Transformations and Permutations in the Triazolopyrimidine Scaffold To Identify the Minimum Pharmacophore Required for Inhibitory Activity against <i>Plasmodium falciparum</i> Dihydroorotate Dehydrogenase
  作者：Alka Marwaha、John White、Farah El_Mazouni、Sharon A Creason、Sreekanth Kokkonda、Frederick S. Buckner、Susan A. Charman、Margaret A. Phillips、Pradipsinh K. Rathod

  DOI：10.1021/jm300351w

  日期：2012.9.13

  Plasmodium falciparum causes approximately 1 million deaths annually. However, increasing resistance imposes a continuous threat to existing drug therapies. We previously reported a number of potent and selective triazolopyrimidine-based inhibitors of P. falciparum dihydroorotate dehydrogenase that inhibit parasite in vitro growth with similar activity. Lead optimization of this series led to the recent identification of a preclinical candidate, showing good activity against P. falciparum in mice. As part of a backup program around this scaffold, we explored heteroatom rearrangement and substitution in the triazolopyrimidine ring and have identified several other ring configurations that are active as PfDHODH inhibitors. The imidazo[1,2-a]pyrimidines were shown to bind somewhat more potently than the triazolopyrimidines depending on the nature of the amino aniline substitution. DSM151, the best candidate in this series, binds with 4-fold better affinity (PfDHODH IC50 = 0.077 mu M) than the equivalent triazolopyrimidine and suppresses parasites in vivo in the Plasmodium berghei model.